In 1979 Birkhahn et al, ((Birkhahn, McMenamy et al. 1979)) described the synthesis of the monoglyceride of acetoacetate which they called monoacetoacetin (MA). The goal was to identify a substrate that would provide a carnitine independent fuel for subjects suffering from sepsis or trauma. The authors listed several reasons for the need for such a compound based on observations of trauma and sepsis patients.
Monoacetoacetin was proposed as a possible compound for parenteral treatment for trauma and sepsis for several reasons, such as that monoacetoacetin is water soluble and does not require emulsification, is metabolized to the safe, naturally occurring compounds of glycerol and acetoacetate, and infusion of monoacetoactin does require a sodium cation, and thus could be administered without increasing sodium load. Direct infusion of ketone bodies would require a sodium cation.
Birkhahn et al. describe the synthesis of MA. MA was synthesized by combining a 1:1 mole ratio of glycerol and diketene and reacted at 80° C. The reaction was stirred for 30 minutes, the product was dissolved in chloroform, washed with water, and separated from solvent under vacuum {Birkhahn, 1978 #412}.
U.S. Pat. No. 5,420,335 entitled “Parenteral nutrients based on water soluble glycerol bisacetoacetates,” concerns novel parenteral nutrient compositions consisting of glycerol with two acetoacetates esterified to the OH groups of the glycerol. This patent teaches a method of synthesis of glycerol bisacetoacetate by the method of mixing diketene with glycerol in a solution of dimethylaminopyridine.
U.S. Pat. No. 5,693,850 entitled “Nutritive water soluble glycerol esters of hydroxybutyric acid” was issued Dec. 2, 1997. This patent describes a process for the production of water soluble glycerol esters useful as parenteral nutrients.
U.S. Patent Application Publication No. 2006/0280721 relates to compositions containing (R)-3-hydroxybutyrate derivatives and the use of such compounds for the AD and similar conditions.
The methods of synthesis of described in the prior art require the use of dangerous compounds, such as diketene which is an explosion hazard. Moreover many organic solvents are toxic and therefore organic solvent contamination in pharmaceutical or nutritional products can be a serious problem. Thus it is important to ensure that pharmaceutical and nutritional products are free from solvent contamination, which introduces additional complications and expense.